{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:37:51Z","timestamp":1789580271134,"version":"build-2803163510"},"reference-count":63,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Auvergne-Rh\u00f4ne-Alpes Regional Council (AURA) and the European Regional Development Fund (ERDF)","award":["#AV0020785"],"award-info":[{"award-number":["#AV0020785"]}]},{"name":"Auvergne-Rh\u00f4ne-Alpes Regional Council (AURA) and the European Regional Development Fund (ERDF)","award":["CAP 20-25"],"award-info":[{"award-number":["CAP 20-25"]}]},{"name":"Auvergne-Rh\u00f4ne-Alpes Regional Council (AURA) and the European Regional Development Fund (ERDF)","award":["ANR-22-CE18-0002"],"award-info":[{"award-number":["ANR-22-CE18-0002"]}]},{"name":"Innopain company","award":["#AV0020785"],"award-info":[{"award-number":["#AV0020785"]}]},{"name":"Innopain company","award":["CAP 20-25"],"award-info":[{"award-number":["CAP 20-25"]}]},{"name":"Innopain company","award":["ANR-22-CE18-0002"],"award-info":[{"award-number":["ANR-22-CE18-0002"]}]},{"name":"ANALGESIA Institute Foundation","award":["#AV0020785"],"award-info":[{"award-number":["#AV0020785"]}]},{"name":"ANALGESIA Institute Foundation","award":["CAP 20-25"],"award-info":[{"award-number":["CAP 20-25"]}]},{"name":"ANALGESIA Institute Foundation","award":["ANR-22-CE18-0002"],"award-info":[{"award-number":["ANR-22-CE18-0002"]}]},{"name":"French government IDEX-ISITE initiative 16-IDEX-001","award":["#AV0020785"],"award-info":[{"award-number":["#AV0020785"]}]},{"name":"French government IDEX-ISITE initiative 16-IDEX-001","award":["CAP 20-25"],"award-info":[{"award-number":["CAP 20-25"]}]},{"name":"French government IDEX-ISITE initiative 16-IDEX-001","award":["ANR-22-CE18-0002"],"award-info":[{"award-number":["ANR-22-CE18-0002"]}]},{"DOI":"10.13039\/501100001665","name":"French National Research Agency","doi-asserted-by":"publisher","award":["#AV0020785"],"award-info":[{"award-number":["#AV0020785"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"French National Research Agency","doi-asserted-by":"publisher","award":["CAP 20-25"],"award-info":[{"award-number":["CAP 20-25"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"French National Research Agency","doi-asserted-by":"publisher","award":["ANR-22-CE18-0002"],"award-info":[{"award-number":["ANR-22-CE18-0002"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>TWIK-related K+ (TREK-1) channels are involved in pain perception and their pharmacological activation has potential for pain relief. The development of new pharmacological tools to study these channels and enrich our knowledge of structure\u2013activity relationships is therefore important. We optimized a high throughput screening method based on thallium flux monitoring for the detection of TREK-1 activators in chemical libraries. We screened 1040 compounds from the French National Essential Chemical Library and identified LPS2336 as a potent TREK-1 activator with an EC50 of 11.76 \u00b5M. Thirty-three LPS2336 analogs were subsequently tested but none of them retained activity on TREK-1. In vivo, LPS2336 produces antinociceptive activity when administered systemically and, to a lesser extent, intracerebroventricularly, but not intrathecally, showing that targeting peripheral TREK-1 channels may be important to produce pain relief, with the interest of reducing potential central adverse effects. LPS2336 was shown to produce sedation and hypothermia with a narrow therapeutic window. As these adverse effects are also observed in TREK-1 knock-out mice, they are likely mediated by off-targets. Our work provides key optimization steps for thallium-based assays and a new pharmacological tool for the study of TREK-1 channels. It also raises the importance of investigating adverse effects in vivo at early stages of drug discovery.<\/jats:p>","DOI":"10.3390\/biom15050740","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T11:50:31Z","timestamp":1747741831000},"page":"740","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["LPS2336, a New TREK-1 Channel Activator Identified by High Throughput Screening"],"prefix":"10.3390","volume":"15","author":[{"given":"Romane","family":"Boyer","sequence":"first","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, Inserm, CHU Clermont-Ferrand, Neuro-Dol, 63000 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romane","family":"Bony","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, Inserm, CHU Clermont-Ferrand, Neuro-Dol, 63000 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxence","family":"Maugis","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, Inserm, CHU Clermont-Ferrand, Neuro-Dol, 63000 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7637-7602","authenticated-orcid":false,"given":"Julien","family":"Schopp","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, Inserm, CHU Clermont-Ferrand, Neuro-Dol, 63000 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Leroux","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, 63000 Clermont-Ferrand, 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Auvergne, CNRS, Clermont Auvergne INP, ICCF, 63000 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9264-7690","authenticated-orcid":false,"given":"Youssef","family":"Aissouni","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, Inserm, CHU Clermont-Ferrand, Neuro-Dol, 63000 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2848-9859","authenticated-orcid":false,"given":"Bruno","family":"Didier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, Laboratoire d\u2019Innovation Th\u00e9rapeutique, LIT UMR 7200, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-0078","authenticated-orcid":false,"given":"Mihaela","family":"Gulea","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, 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